Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

Li, Mengyu; Yeung, Chris Ho Ching; Schooling, CM

doi:10.3389/fgene.2021.680646

Cited by 13 publications

(13 citation statements)

References 44 publications

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“…MIP1b is a major proinflammatory factor, acting as a chemoattractant for natural killer cells [104]. This association has been reported previously [105], with studies suggesting that MIP1b is a key mediator in the immune response against COVID-19 [106]. Also, in line with our findings of respiratory support/death due to COVID-19 decreasing levels of NEP, NEP protects against pulmonary inflammation and fibrosis [107].…”

Section: Plos Geneticssupporting

confidence: 88%

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

et al. 2022

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In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12–1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80–0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86–0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.

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Section: Plos Geneticssupporting

confidence: 88%

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

et al. 2022

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“…Mendelian randomization studies have explored the role of a wide range of anthropometrics and biomarkers in COVID-19 risk, including anthropometrics, blood pressure, coagulation factors, cytokines, inflammatory markers, glycaemic traits, haematological traits, lipids, liver functions, renal functions and vitamins. 27 , 31–33 , 35 , 38–40 , 42 , 44–47 , 49 , 52 , 53 , 55 , 58–60 , 62 , 64 , 65 Consistent evidence suggested that obesity [higher body mass index (BMI) and trunk fat ratio] was associated with higher COVID-19 risk 27 , 32 , 38 , 42 , 45 , 53 and one study also showed that increase in height was associated with higher risk of COVID-19 susceptibility. 27 Consistent evidence showed systolic and diastolic blood pressure to have no role in COVID-19 risk, 27 , 32 , 42 , 49 , 53 although one study found that higher pulse pressure was associated with higher risk of COVID-19 hospitalization in people of mixed ancestry but not of European ancestry.…”

Section: Resultsmentioning

confidence: 96%

“… 27 Consistent evidence showed systolic and diastolic blood pressure to have no role in COVID-19 risk, 27 , 32 , 42 , 49 , 53 although one study found that higher pulse pressure was associated with higher risk of COVID-19 hospitalization in people of mixed ancestry but not of European ancestry. 49 Coagulation factors [higher von Willebrand factor (VWF) and lower disintegrin and metalloprotease with a thrombospondin type 1 motif member 13 (ADAMTS13)] 64 and lower cytokine [macrophage inflammatory protein 1 b (MIP1b)] 44 were associated with higher risk of COVID-19. The inflammatory marker C-reactive protein (CRP) was nominally associated with higher risk of COVID-19 hospitalization and susceptibility in one study 42 but not another study.…”

Section: Resultsmentioning

confidence: 99%

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

Luo

Liang

Wong

et al. 2022

International Journal of Epidemiology

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Background To summarize modifiable factors for coronavirus disease 2019 (COVID-19) suggested by Mendelian randomization studies. Methods In this systematic review, we searched PubMed, EMBASE and MEDLINE, from inception to 15 November 2021, for Mendelian randomization studies in English. We selected studies that assessed associations of genetically predicted exposures with COVID-19-related outcomes (severity, hospitalization and susceptibility). Risk of bias of the included studies was evaluated based on the consideration of the three main assumptions for instrumental variable analyses. Results We identified 700 studies through systematic search, of which 50 Mendelian randomization studies were included. Included studies have explored a wide range of socio-demographic factors, lifestyle attributes, anthropometrics and biomarkers, predisposition to diseases and druggable targets in COVID-19 risk. Mendelian randomization studies suggested that increases in smoking, obesity and inflammatory factors were associated with higher risk of COVID-19. Predisposition to ischaemic stroke, combined bipolar disorder and schizophrenia, attention-deficit and hyperactivity disorder, chronic kidney disease and idiopathic pulmonary fibrosis was potentially associated with higher COVID-19 risk. Druggable targets, such as higher protein expression of histo-blood group ABO system transferase (ABO), interleukin (IL)-6 and lower protein expression of 2′-5′ oligoadenylate synthetase 1 (OAS1) were associated with higher risk of COVID-19. There was no strong genetic evidence supporting the role of vitamin D, glycaemic traits and predisposition to cardiometabolic diseases in COVID-19 risk. Conclusion This review summarizes modifiable factors for intervention (e.g. smoking, obesity and inflammatory factors) and proteomic signatures (e.g. OAS1 and IL-6) that could help identify drugs for treating COVID-19.

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“…Inflammation, in particular, has received much attention regarding COVID‐19 because of its relevance to the immune system, and may explain why certain people have a poorer COVID‐19 prognosis [ 39 ]. Genetic evidence for associations of inflammatory markers with COVID‐19 is limited [ 40 ]. Nevertheless, randomized controlled trials of interleukin (IL)‐6R antagonists, such as tocilizumab, suggest that it may be an effective treatment [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Association of smoking, lung function and COPD in COVID‐19 risk: a two‐step Mendelian randomization study

Yeung

et al. 2022

Addiction

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Background and Aims Smoking increases the risk of severe COVID‐19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions. Design Mendelian randomization study using summary statistics from genome‐wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings. Setting GWAS which included international consortia, FinnGen and UK Biobank. Participants The sample size ranged from 193 638 to 2 586 691. Measurements Genetic determinants of life‐time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV 1 )], chronic obstructive pulmonary disease (COPD) and different severities of COID‐19. Results Smoking increased the risk of COVID‐19 compared with population controls for overall COVID‐19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life‐time smoking index, 95% confidence interval (CI) = 1.11–1.27], hospitalized COVID‐19 (OR = 1.67, 95% CI = 1.42–1.97) or severe COVID‐19 (OR = 1.48, 95% CI = 1.10–1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations. Conclusion There is genetic evidence that smoking probably increases the risk of severe COVID‐19 and possibly also milder forms of COVID‐19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID‐19 risk.

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Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study

Cited by 13 publications

References 44 publications

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

Association of smoking, lung function and COPD in COVID‐19 risk: a two‐step Mendelian randomization study

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